It is well known that alpha-arylalkanoic acids represent a large class of compounds, many of which are useful as anti-inflammatory and analgesic drugs.
Among these, 2-(4-isobutylphenyl)-propionic acid known as Ibuprofen, 2-(3-phenoxyphenyl)-propionic acid known as Fenoprofen, 2-(2-fluoro-4-diphenyl)-propionic acid known as Flurbiprofen, 2-[4-(2-thienylcarbonyl)-phenyl]-propionic acid known as Suprofen, 2-(6-methoxy-2-naphthyl)-propionic acid, whose S(+) isomer is known as Naproxen, and still others may be mentioned.
The preparation of .alpha.-aryl propionic acids has so far followed the so-called classic chemical methods which employ as starting material aryl alkyl ketone derivatives and are known by such names as Darzen's reaction, Willgerodt's reaction, Arndt-Eistert's reaction and Friedel-Crafts reaction. Of these, Darzen's reaction constitutes more or less the generally accepted basic method for the preparation of .alpha.-aryl propionic acids. [D. R. White (The Upjohn Company) U.S. Pat. No. 3,975,431 (1976); Chemical Abstracts 86,5168 w].
More recently, newer methods have been proposed for the preparation of .alpha.-aryl propionic acids. These include Gassman's procedure and certain nucleophilic substitution and chemical rearrangement of propionic acid derivatives [P. G. Gassman and T. J. Van Bergen, Journal of the American Chemicals Society, 96(17), 5508 (1974); G. P. Stahly, B. C. Stahly and K. C. Lilge, Journal of Organic Chemistry, 49 579 (1984); M. S. Newman and B. J. Magertein, Organic Reactants V, 413 (1949); Brown, E. V. Synthesis, 358 (1975); S. Yoshimura, S. Takahashi and M. Ichino (Kohjin Company), Japanese Pat. No. 76,36,432 (Mar. 27, 1976); and Chemical Abstract 85,123596 m].
While any of these preparation schemes produce the desired aryl propionic acid, very little attention has been paid to the methods of processing the materials produced. Thus, one of the highest commercial volume profen drugs, ibuprofen, is typically produced in a crystalline form that flows poorly. (It should be noted that ibuprofen crystalline flow is directly related to total surface area and, therefore, crystal size, i.e. large crystals, promotes flow because of decreased surface area.) As a result, preparations containing this material disadvantageously adhere to the molding surfaces of tablet punches and dies during processing.
In U.S. Pat. No. 4,476,248, incorporated herein by reference, the course of the above disadvantageous behavior was established as due to the size and the shape of the ibuprofen crystals. This patent discloses that acicular (needle) or lath (blade) crystals are to be avoided and cubic or spherical shapes are desirable. These latter shapes produce greatly enhanced crystalline flow properties of the final ibuprofen. The patent further discloses that when ibuprofen is dissolved in and crystallized from a solution of any solvent which has a hydrogen bonding parameter (SH) equal or greater than (.gtoreq.) 8 Hilderbrand units, e.g., a C.sub.1 to C.sub.3 alkanol, there is obtained crystalline ibuprofen having larger particle size, on average, as compared to crystalline ibuprofen obtained by crystallizing ibuprofen from heptane or hexane, the usual commercially used solvents.
While this patent extols the economic advantages of such improved flow produced from the larger particle size crystalline ibuprofen, the extra processing step, i.e., the step required to-first remove the inert solvent (typically a hydrocarbon one) used in the above-disclosed processes for preparing the .alpha.-aryl propionic acid, is undesirably costly and time and equipment consuming.
Accordingly, there is a need for preparing crystalline ibuprofen that has improved flow properties over that of the prior art.